Crosslinked anion-exchange resin or salt thereof and phosphorus adsorbent comprising the same

ABSTRACT

An cross-linked anion exchange resin or a salt thereof obtained by reacting a polymer (A) having amino and/or imino groups in the total number of two or more per molecule with a compound (B) having two or more functional groups capable of reacting with amino and/or imino group contained in the polymer (A). The resin or salt has a water absorption ratio of 4.0 or lower.

TECHNICAL FIELD

[0001] The present invention relates to a crosslinked anion exchangeresin or a salt thereof which is crosslinked to an optimal degree ofcrosslinking by a compound having two or more functional groups capableof reacting to amino or imino groups. The crosslinked anion exchangeresin has the optimal degree of crosslinking and thus a high adsorptioncapacity with respect to phosphorus compounds such as phosphates, andcan be used as a phosphorus adsorbent for use in purification of waterin lakes, lagoons, rivers, or the like, or as a preventive and/ortherapeutic agent of hyperphosphatemia for use in medical treatment.

BACKGROUND ART

[0002] It is known that a patient with renal dysfunction gradually losesa capability to excrete the body's phosphorus into urine due to adecline in renal functions associated with a deterioration of the renallesion and results in hyperphosphatemia. In patients who suffer from thecondition of hyperphosphatemia for an extended period, phosphorusaccumulated in the body induces various hazards such as a decrease inserum calcium, and thus medical treatment of hyperphosphatemia wasindispensable for the patients.

[0003] For the treatment of hyperphosphatemia, a therapy by oraladministration of a phosphorus adsorbent has been practiced as well asthe dietetic therapy. The therapy by oral administration of a phosphorusadsorbent is based on a function of the phosphorus adsorbent to adsorband trap phosphate ions present in food ingested by the patient, thussuppressing intake and accumulation of phosphorus in the body andconsequently reducing phosphorus concentration in blood. Currently,three kinds of medicines, aluminum preparations, calcium preparationsand magnesium preparations, are mainly used as the oral phosphorusadsorbent. But since the medicines are necessarily administrated for aprolonged term for those patients with renal failure, the aluminumpreparations containing aluminum hydroxide raise a problem of adversereactions such as aluminum encephalopathy and aluminum osteopathyinduced by the uptake of aluminum into the patient body. Additionally,the calcium preparations (calcium carbonate, calcium acetate) have thesimilar problem since they have lower phosphorus adsorption capacitiescompared to the aluminum preparations, demanding an increasedadministration of the medicine and consequently resulting in an uptakeof more calcium possibly leading to hypercalcemia. Moreover, themagnesium preparations (magnesium carbonate) have a problem ofhypermagnesemia, as with the calcium preparations.

[0004] In view of the problems associated with the conventional oralphosphorus adsorbents for medicine, recently, methods to use an anionexchange resin as the phosphorus adsorbent have been studied. Forexample, Japanese PCT International Publication No. 9-504782(WO95/05184) discloses that an anion exchange resin of polyallylaminehydrochloride crosslinked with epichlorohydrin can be used as amedicinal phosphoric acid adsorbent. Additionally, in JapaneseUnexamined Patent Publication No. 9-295941 was disclosed that2-methylimidazole-epichlorohydrin copolymer, cholestyramine and the likethat were used as bile acid adsorbents can also be used as medicinalphosphorus adsorbents, and in Japanese PCT International Publication No.8-506846 (WO96/25440) that an anion exchange resin having guanitidyl(sic) groups may adsorb phosphoric acid.

[0005] Although these anion exchange resins exhibit sufficientadsorption capacities with respect to phosphate ion, there were someresins that should be administered in a greater amount to raise thetherapeutic effect. Additionally, according to a survey in the U.S.,about 25% of the renal failure patients were concurrently suffering fromhyperlipemia, while the remaining 75% patients were not required todecrease the blood cholesterol level. But among the conventionalmedicinal phosphorus adsorbents, there were some that adsorb not onlyphosphoric acid, but also organic acids including raw materials ofcholesterol such as bile acids (e.g., glycocholic acid), andconsequently induce the hazard of a decrease in the blood cholesterollevel. Therefore, there was a need to raise both the phosphoric acidadsorption capacity and the phosphoric acid selectivity.

[0006] Thereupon, objects of the present invention are to find acrosslinked anion exchange resin that is excellent both in thephosphorus adsorption capacity and the selectivity to phosphorus, and toprovide a phosphorus adsorbent comprising the crosslinked anion exchangeresin or the salt thereof, by studying kinds of anion exchange resin andeffects of crosslinking with crosslinking agents.

DISCLOSURE OF THE INVENTION

[0007] A crosslinked anion exchange resin or a salt thereof of thepresent invention features in that it is the crosslinked anion exchangeresin or a salt thereof which is obtained by reacting a polymer (A)having amino and/or imino groups in the total number of two or more permolecule with a compound (B) having two or more functional groupscapable of reacting with the amino and/or imino groups and has a waterabsorption ratio of 4.0 or less. It is because it was found that thepolymer (A) with the compound (B) through two or more amino or iminogroups above a specific crosslinking degree provided a crosslinked anionexchange resin excellent both in the phosphorus adsorption capacity andthe selectivity to phosphorus. The crosslinked anion exchange resin hasan excellent phosphorus adsorbing capacity also in a salt from such ashydrochloride. Meanwhile, the “amino or imino groups” in the polymer (A)of the present invention include a nitrogen atom of tert-amine, and thepolymers (A) include polymers having the “amino or imino groups” abovein the main chains and/or in the branched chains.

[0008] A crosslinked anion exchange resin or a salt thereof which isobtained by reacting a polymer (A) having amino and/or imino groups inthe total number of two or more per molecule with a compound (B) havingtwo or more functional groups capable of reacting with the amino and/orimino groups in the absence of a solvent or in the presence of annonaqueous solvent is also embraced in the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009]FIG. 1 is a bar graph showing the results of measurement ofadsorption properties and water absorption ratio determined inEXPERIMENTAL EXAMPLE 11.

[0010]FIG. 2 is a bar graph showing a part of the results in FIG. 1.

[0011]FIG. 3 is a bar graph showing the results of measurement ofadsorption properties determined in EXPERIMENTAL EXAMPLE 17.

[0012]FIG. 4 is a bar graph showing the results of measurement ofincrease in phosphorus excreted in urine determined in EXPERIMENTALEXAMPLE 18.

[0013]FIG. 5 is a bar graph showing the results of phosphorusconcentration in blood determined in EXPERIMENTAL EXAMPLE 19.

[0014]FIG. 6 is a bar graph showing the results of protein excretioninto urine determined in EXPERIMENTAL EXAMPLE 19.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As a consequence of intensive studies on the method forincreasing the phosphorus adsorption capacity and the selectivity tophosphorus, the present inventors have found that it was possible toincrease the phosphorus selectivity of an anion exchange resin bycrosslinking the resin to a higher degree of crosslinking by using agreater amount of a crosslinking agent. Additionally, it was found thatthe amount of the crosslinking agent used in preparation had a goodcorrelation with the water absorption ratio of the resulting resin, andthat by setting an upper limit to the water absorption ratio, it waspossible to prepare a crosslinked anion exchange resin or a salt thereofexcellent in both the phosphorus adsorption capacity and the selectivityto phosphorus. Further, the inventors have also found that it waseffective to conduct the crosslinking reaction in the absence of asolvent or in a presence of a nonaqueous solvent for obtaining the anionexchange resin for phosphorus adsorption having a water absorption ratioof 4.0 or less, and thus completed the present invention.

[0016] Namely in first aspect of the present invention, the crosslinkedanion exchange resin or the salt thereof is characterized in that it isobtained by reacting a polymer (A) having amino and/or imino groups witha compound (B) having two or more functional groups capable of reactingwith amino and/or imino groups, and has a water absorption ratio of 4.0or less. Additionally in a second invention of the present invention,the crosslinked anion exchange resin or the salt thereof ischaracterized in that it is obtained in a reaction of polymer (A) havingamino and/or imino groups and a compound (B) having two or morefunctional groups capable of reacting with the amino and/or imino groupsin the absence of a solvent or in the presence of a nonaqueous solvent.

[0017] The polymer (A) has preferably a number averaged molecular weightof 200 or more. In a favorable embodiment of the present invention, thepolymer (A) is at least one or more polymer selected from the groupconsisting of polyalkyleneimine, polyallylamine, polyvinylamine andallylamine-vinylamine copolymer. Meanwhile, an amine value of thepolymer (A) is preferably 8 to 67 mg eq/g.

[0018] The phosphorus adsorbent comprising the crosslinked anionexchange resin and/or the salt thereof of the present invention may beused as a phosphorus adsorbent for purification of water in lakes,lagoons and rivers as well as of wastewater, and also as a phosphorusadsorbent for medicines. In particular, a medicine comprising thecrosslinked anion exchange resin or the pharmaceutically acceptable saltthereof exerts a beneficial medicinal effect as a preventive and/ortherapeutic agent of hyperphosphatemia.

[0019] The term, “polymer”, according to the present invention is notintended to mean only a homopolymer, but also include copolymers that donot impede the present inventive object and multi-component copolymersconsisting of three or more components. Hereinafter, the presentinvention will be described in detail.

[0020] The crosslinked anion exchange resin or the salt thereof of thepresent invention can be obtained from polymer (A) having amino or iminogroups in the total number of two or more in a molecule. Namely, thepolymer (A) is not limited so far as the polymer has two or more aminogroups, two or more imino groups, or one or more amino or imino groupsrespectively in a molecule. It is because the amino and/or imino groupsare the sites being crosslinked with the compound (B). Since thecrosslinking may become insufficient when there is only one crosslinkingsite in a polymer molecule, a polymer having amino group and/or iminogroup in the total number of two or more is preferably selected as thepolymer (A). Even after the crosslinking reaction, the polymer still hasamino or imino groups that are not involved in the crosslinkingreaction, and thus retains the anion exchange capacity.

[0021] Molecular weight of the polymer (A) above is not limitedparticularly, but preferably 200 or more as number averaged molecularweight. A polymer having the molecular weight of below 200 is notfavorable since the polymer provides a fragile crosslinked anionexchange resin with an inferior strength. The lower limit of themolecular weight thereof is more preferably 500 or more as numberaveraged molecular weight. On the other hand, even though a polymerhaving a higher molecular weight is not particularly inconvenient, apolymer having an excessively high molecular weight may cause anentanglement of the polymer chains and thus affect the ion exchangeproperty and the phosphorus adsorption property. Therefore, a polymerhaving a number averaged molecular weight of 10 million or less isrecommended. The upper limit of the molecular weight is more preferably1 million or less, more preferably 500 thousand or less, and mostpreferably 100 thousand or less.

[0022] As described above, the polymer (A) above has amino and/or iminogroups in the total number of two or more. But since it is necessary toraise a degree of crosslinking by adding more crosslinking agent in thereaction mixture for obtaining a highly crosslinked polymer having awater absorption ratio of 4.0 or less, the polymer (A) has preferablymore amino and/or imino groups where the crosslinking reaction possiblyoccurs. Therefore, polymers having alkyleneimine, vinylamine, orallylamine (including the salts thereof) as a main constitutionalmonomer, i.e., polyalkyleneimine, polyvinylamine, and polyallylamine,are most preferable. Of course, polymers comprising two or more polymersselected from alkyleneimine, vinylamine and allylamine may be also used,and a vinylamine-allylamine copolymer is most preferable. Additionally,modified resins (derivatives) prepared by reacting these amine polymerswith ethylene oxide, glycidol or the like can also be used.

[0023] Meanwhile, as the polyalkyleneimine, polyethyleneimine and/orpolyethylene-propyleneimine or the like can be most preferably used, andan alkyleneimine having an alkylene group of up to 8 carbons may also beused as a (co)monomer. Further, the polyethyleneimines are commerciallyavailable for example in trade name “EPOMIN SP” series from NipponShokubai Co., Ltd. (e.g., “EPOMIN SP-006”, “EPOMIN SP-018”, “EPOMINSP-200”, etc.), and these products may be used as the polymer (A) forthe crosslinking.

[0024] Additionally, copolymers prepared by copolymerization ofalkyleneimine, vinylamine, or allylamine with other monomers may also beused as the polymer (A). The other monomers that may be copolymerizedare, for example, monomers containing amino group(s) such asdimethylaminoethyl(meth)acrylate, diethylaminoethyl(meth)acrylate,dimethylaminopropyl(meth)acrylate, diethylaminopropyl(meth)acrylate,2-hydroxydimethylaminopropyl(meth)acrylate, aminoethyl(meth)acrylate,etc, or the salts thereof such as hydrochloride, hydrobromide, sulfate,nitrate, acetate, propionate, etc., [herein, “(meth)acrylate” meansacrylate and methacrylate]; monomers containing amide group(s) such as(meth)acrylamide, t-butyl(meth)acrylamide, etc.; monomers containinghydroxyl group(s) such as hydroxyethyl(meth)acrylate, polyethyleneglycolmono(meth)acrylate, polyethyleneglycol monoisoprenolether,polyethyleneglycol monoallylether, hydroxypropyl(meth)acrylate,polypropyleneglycol mono(meth)acrylate, polypropyleneglycolmonoisoprenolether, polypropyleneglycol monoallylether, α-hydroxyacrylic acid, N-methylol(meth)acrylamide, vinylalcohol, allylalcohol,3-methyl-3-buten-1-ol (isoprenol), glycerol monoallylether, etc.;(meth)acrylates such as methyl(meth)acrylate, ethyl(meth)acrylate, etc.;or styrene, α-methylstyrene, vinyl acetate, vinylpyrrolidone, vinylethers, etc. Additionally, weak basic anion exchange resins known in theart containing amino or imino groups may also be used as the polymer(A).

[0025] A preferable range of the total amount of the amino and/or iminogroups, defined by an amine value per gram of the polymer (A), is 8 to67 mg eq/g. A polymer (A) having the amine value of smaller than 8 mgeq/g tends to yield a product insufficient in crosslinking. The morepreferable lower limit of the amine value is 10 mg eq/g, and the upperlimit is 25 mg eq/g. The amine value of the polymer (A) can bedetermined, for example, by neutralization titration in a nonaqueoussolution. Concretely, the amine value can be determined by the followingmethod.

[0026] (1) A solution of 0.5N p-toluenesulfonic acid in acetic acid(hereinafter, abbreviated as PTS) is prepared. About 0.3 g of sodiumcarbonate (purity: A mass %) is weighed (accurately to a 0.1 mg order)(sodium carbonate amount: M mg), and dissolved in 10 ml of methanol and30 ml of acetic acid. The resulting solution is titrated with PTS, and afactor F of PTS is calculated from the titer (V₁ ml). The factor F ofPTS is calculated by the following equation.

F=(M×A)/(100×105.99×2×V ₁).

[0027] (2) About 0.2 g of polymer (A) (resin solid content: N mass %) isweighed (accurately to a 0.1 mg order) (amount: S g), and dissolved in10 ml of methanol. After 30 ml of acetic acid was added to the solution,the resulting solution was titrated with PTS above and the amine valueof polymer (A) is calculated from the titer (V₂ ml). The amine value (mgeq/g) per g of the polymer (solid content) is calculated by thefollowing equation by using the factor F of PTS obtained in (1).

Amine value=(0.5×F×V ₂)/(S×N×10).

[0028] According to the present invention, a crosslinked anion exchangeresin crosslinked so as to have a water absorption ratio of 4.0 or lessis obtained by reacting a polymer (A) having amino and/or imino groupswith a compound (B), used as a crosslinking agent, having two or morefunctional groups capable of reacting the amino or imino groups.Examples of the compound (B) include the following compounds.

[0029] (1) Compounds having vinyl groups capable of the Michael additionreaction and carboxylic ester groups; the vinyl groups capable of theMichael addition reaction accept nucleophilic additions of amino or animino groups in the polymer (A), making the polymer (A) and the compound(B) bind to each other (Michael addition-type reaction). Additionally,since the carboxylic ester groups of the compound (B) also react withother amino and/or imino groups forming amide bonds, a reaction betweenthe compound (B) with amino and/or imino groups in different moleculesof the polymer (A) yields a crosslinked polymer in which molecules ofthe polymer (A) are crosslinked with the compound (B).

[0030] Concretely, favorable examples of the compound (B) are(meth)acrylic esters, fumaric mono- or diesters, maleic mono- ordiesters, itaconic mono- or diesters and so on, respectively havingester groups such as alkylesters, having 1 to 10 carbons,cycloalkylesters, benzylesters, etc. Methyl acrylate is most favorableamong the examples above in view of the succeeding processes necessaryto remove alcohol released upon formation of the amide bonds and of thephosphorus adsorption capacity per weight of the resulting phosphorusadsorbent.

[0031] (2) Epihalohydrins; when the amino or imino groups in the polymer(A) are present in an inorganic salt form, epihalohydrins form abisammonium salt therewith and make the polymer (A) crosslinked.Specific examples of the epihalohydrins are epichlorohydrin,epibromohydrin, etc.

[0032] (3) Compounds having two or more epoxy groups; the two or moreepoxy groups in this compound react respectively with two or more aminoor imino groups, crosslinking the polymer (A). Specific examples of thecompound are diglycidylethers such as 1,4-butanediol diglycidylether,1,2-ethanediol diglycidylether, bisphenol A diglycidylether, etc.

[0033] (4) Compounds having two or more isocyanate groups; the twoisocyanate groups in this compound react respectively with two or moreamino or imino groups, crosslinking the polymer (A). Specific examplesof the compound are tolylene diisocyanate, diphenylmethane diisocyanate,etc.

[0034] (5) Compounds having two or more acid chloride groups; the acidchloride groups react respectively with the amino or imino groups.Specific examples of the compounds are succinyl dichloride, etc.Additionally, acryloyl chloride reacts with the amino or imino groups atthe acid chloride portion and also at the acryloyl portion in theMichael addition reaction.

[0035] (6) Compounds having two or more carboxylic ester groups ortetrabasic acid dianhydrides; the carboxylic ester groups or acidanhydride groups react with amino or imino groups forming amide bonds.Specific examples of the compound are saturated carboxylic alkylesterssuch as dimethyl succinate, dimethyl malonate, etc., and tetrabasic aciddianhydrides such as pyromellitic dianhydride, etc, or the like.

[0036] (7) Dihalogenated hydrocarbons; the compounds react with amino orimino groups forming ammonium salts. Specific examples are1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, etc.

[0037] The condition for the crosslinking reaction of polymer (A) withthe above compound (B) may be selected adequately according to the kindsof the polymer (A) and the compound (B). For example, since thereactions of epihalohydrins with amino or imino groups proceed veryrapidly, a reaction in the absence of a solvent is preferably carriedout at around 0° C., the Michael addition reaction is at roomtemperature (25° C.) level, and the amide-bond forming reaction ispreferably conducted under heating. The reaction period is not limitedbut usually about 1 to 100 hours. The reaction product is, afterconverted to a salt if desired by e.g., neutralization in an aqueoushydrochloric acid solution, dried by the method well known in the art toyield a crosslinked anion exchange resin (in the salt form). The driedresins may be further crushed according to the application thereof.

[0038] It was found that it was difficult to obtain a crosslinked anionexchange resin or a salt thereof having the water absorption ratio of4.0 or less when the crosslinking reaction of the polymer (A) with thecompound (B) as crosslinking agent was conducted in a solvent mainlycontaining water especially when the compound (B) reactive to water wasused, and that the crosslinking reaction was preferably conducted in theabsence of a solvent or in the presence of a nonaqueous solvent. Fromthis viewpoint, the present invention includes a phosphorus adsorbentusing a crosslinked anion exchange resin or a salt thereof that isprepared by the crosslinking reaction of polymer (A) with compound (B)in the absence of a solvent or in the presence of a nonaqueous solvent.

[0039] In the case where a polymer liquid at room temperature such aspolyethyleneimine or the like is used as the polymer (A), the solvent isnot required and thus the crosslinking reaction is preferably conductedin the absence of a solvent. In the case where a polymer highly viscousor solid at ordinary temperature is used as the polymer (A), thecrosslinking reaction described above may be conducted using anonaqueous solvent as needed. The nonaqueous solvent means a solventhaving 3 mass % or less water therein. When a solvent containing waterbeyond 3 mass % is used, it becomes difficult to obtain the desireddegree of crosslinking, due to the reactions with water of functionalgroups in, e.g., the compounds containing epoxy groups such asepihalohydrins, diglycidylethers, the compounds containing isocyanategroups or the like.

[0040] As the solvent may be used a solvent that does not participate inthe crosslinking reaction and can solubilize the polymer (A) and thecompound (B) providing a homogeneous reaction environment, or a solventthat does not solubilize but disperse the polymer (A) and the compound(B) providing an heterogeneous reaction environment. Specific examplesof the former solvent include lower alcohols such as methanol, ethanol,isopropanol, etc., ethers such as tetrahydrofuran, 1,4-dioxane,isopropylether, etc., aromatic hydrocarbon solvents such as benzene,toluene, etc., and so on when methyl acrylate is used as the compound(B), and ethers such as tetrahydrofuran, 1,4-dioxane, isopropylether,etc., aromatic hydrocarbon solvents such as benzene, toluene, etc., andso on when epichlorohydrin is used as the compound (B). The lattersolvent may be properly selected according to the kind of the compound(B), and specific examples thereof are aliphatic or alicyclichydrocarbon solvents such as n-hexane, cyclohexane, heptane, etc., whenepichlorohydrin is used as the compound (B).

[0041] Compound (B) used as a crosslinking agent may be preferably addedin an amount properly selected so that the crosslinked anion exchangeresin or the salt thereof obtained has the water absorption ratio of 4.0or less. The amount is also carefully selected for providing thecrosslinked resin or the salt thereof with a desired phosphorusadsorption capacity and the selective adsorption property to phosphorus.Water absorption ratio of the present invention is a value determined bythe steps consisting of enclosing a predetermined amount of an anionexchange resin sample in a porous container such as a non-woven fabricbag, immersing the container in pure water for 24 hours, dehydrating thecontainer at 1300 rpm for 3 minutes in a centrifuge, the mass of thesample being measured, the mass after water absorption being divided bythe mass before water absorption, and the value thus obtained beingfurther subtracted by 1.

[0042] A crosslinked anion exchange resin or a salt thereof having thewater absorption ratio beyond 4.0 cannot have a high level of phosphorusadsorption capacity and phosphorus selective adsorption property.Therefore, the upper limit of the water absorption ratio is set at 4.0in the present invention. The lower limit thereof is not particularlylimited and may be at 0. The polymer (A) of the present invention is ahydrophilic polymer having amino or imino groups, and thus a low waterabsorption ratio indicates a high degree of crosslinking. The reason forincreases in the phosphorus adsorption capacity and the phosphorusselective adsorption associated with an increase in the degree ofcrosslinking is not clear, but it is contemplated that the crosslinkingand the hydrogen bonding by the compound (B) combined confine the resininto a considerably dense three dimensional structure and phosphorusadsorbed therein is securely contained in the three dimensional network,and that the lattices formed by the three dimensional network aresufficiently large for penetration of phosphate ions, but not forpenetration of higher molecular weight organic acids such as glycocholicacid.

[0043] The upper limit of the water absorption ratio is preferably 3.8,more preferably, 3.6, 3.4, 3.0 in the order, and most preferably 2.8.While, the lower limit thereof is preferably 0.1, more preferably 0.2,and most preferably 0.4.

[0044] In order to make the water absorption ratio 4.0 or less, thecompound (B) is preferably used in an amount of 2 to 50 mol % withrespect to total moles of the amino or imino groups in the polymer (A).With the compound (B) being used in an amount of less than 2 mol %, theresulting polymer may have the water absorption ratio of more than 4.0,and may not have the desired phosphorus adsorption capacity due toinsufficient crosslinking. Even when the compound (B) having two or morefunctional groups is added in an amount of 50 mol % in a reactionsystem, there still remain amino or imino groups left that are notinvolved in the crosslinking reaction, as are usually found in generalchemical reactions. Further, amino or imino groups involved in theMichael addition reaction provide secondary and/or tertiary amines thatare still capable of ion exchanging. Therefore, the upper limit of thecompound (B) to be added is set as 50 mol %. The upper limit of thecompound (B) to be used is more preferably 40 mol % or less with respectto total moles of the amino or imino groups in the polymer (A), morepreferably 30 mol % or less, and particularly preferably 25 mol % orless.

[0045] The crosslinked anion exchange resin of the present invention maybe used as an anion exchange resin containing the amino or imino groupsas they are in the free base form. Additionally, the crosslinked anionexchange resin may be converted to a salt thereof. Example of the saltinclude salts of inorganic acids such as hydrochloric acid, sulfuricacid, bicarbonic acid, carbonic acid, nitric acid, phosphoric acid (notfavorable when used as a phosphorus adsorbent), etc.; organic acidscontaining a carboxyl group(s) such as oxalic acid, tartaric acid,benzoic acid, p-methoxybenzoic acid, p-hydroxybenzoic acid, valericacid, citric acid, glyoxylic acid, glycolic acid, glyceric acid,glutaric acid, chloroacetic acid, chloropropionic acid, cinnamic acid,succinic acid, acetic acid, lactic acid, pyruvic acid, fumaric acid,propionic acid, 3-hydroxypropionic acid, malonic acid, butyric acid,isobutyric acid, amino acids, imidinoacetic acid, malic acid, isethionicacid, citraconic acid, adipic acid, itaconic acid, crotonic acid,salicylic acid, gluconic acid, glucuronic acid, gallic acid, sorbicacid, etc.; and organic acids containing a sulfonic acid group such assulfoacetic acid, methanesulfonic acid, ethanesulfonic acid, etc. Thecrosslinked anion exchange resin may also be partially chelated.

[0046] Particularly when used in the medical application, thecrosslinked anion exchange resin should be converted to apharmaceutically acceptable salt, and thus salts including halides;inorganic acids salts such as hydrochloride, sulfate, bicarbonate,carbonate, etc.; organic acids such as formate, acetate, propionate,malonate, succinate, fumalate, ascorbate, glucuronate, aspartate, aminoacid salts such as glutamate, etc., are recommended. Among them, ahalide ion as the counter ion, in particular chloride ion, is favorablesince the crosslinked anion exchange resin has the highest phosphateadsorption capacity when it has a chloride ion.

[0047] The crosslinked anion exchange resin or the salt thereof of thepresent invention (hereinafter, referred to solely as the “crosslinkedanion exchange ;resin”) may be used in all areas where the weak basicanion exchange resins known in the art are utilized. Additionally, thecrosslinked anion exchange resin of the present invention is extremelyuseful as a phosphorus adsorbent since it has an excellent phosphorusadsorption capacity.

[0048] The crosslinked anion exchange resin of the present invention hasan excellent phosphate-ion adsorbing capacity, and thus may be used, inindustrial applications, for removal of phosphate ions in water oflakes, lagoons, and rivers, or in wastewater. In this case, thecrosslinked anion exchange resin may be used as it is or attached on asupport known in the art, as the phosphorus adsorbent. Specificpurification methods include, for example, a method by filling thecrosslinked anion exchange resins in a treatment tank and subsequentlyintroducing liquid to be treated therein, and a method to sink a porouscontainer such as a bag filled with the anion exchange resins in lakes,lagoons or the like to be treated. Additionally, the crosslinked anionexchange resins may be used in combination with other phosphorusadsorbents or other adsorbents, and in such a case, the crosslinkedanion exchange resin is preferably contained in the phosphorus adsorbentof the present invention in an amount of 0.1 mass % or more from aviewpoint of the phosphorus adsorption property. The phosphorusadsorbent of the present invention can be also used for removal ofphosphorus in food during food processing, and may be applied for soilimprovement.

[0049] The phosphorus adsorbent of the present invention can also beused in the medicinal application and is extremely useful particularlyas a preventive and therapeutic agent of hyperphosphatemia for renalfailure patients. Namely when the phosphorus adsorbent comprising thecrosslinked anion exchange resin of the present invention isadministered as a medicine to a patient, though the anion exchangeresins in the medicine are conveyed through the gastrointestinal tractand finally excreted, the crosslinked anion exchange resins adsorb andtrap phosphate ions contained in food ingested by the patient during thetransport in the gastrointestinal tract, suppressing the uptake andaccumulation of phosphorus in the body, consequently leading to adecrease in phosphorus concentration in the blood of the patient.Additionally, the resin itself is unchanged during the aforementionedprocess except that the resin exerts the phosphorus adsorption action,and thus does not lead to adverse reactions of the conventional oralphosphorus adsorbents, such as aluminum preparations and the like.

[0050] Furthermore, the crosslinked anion exchange resin of the presentinvention has a high selectivity to phosphate ions and a low adsorptioncapacity to organic acids derived from cholesterol such as glycocholicacid or the like contained in the bile acids secreted from the bile ductinto the small intestine. Therefore, the crosslinked anion exchangeresin does not have an inconvenience in that the resin loses part of itsinherent phosphorus adsorption capacity by adsorbing glycocholic acid,and retains and exerts its excellent phosphorus adsorption action.Additionally, the crosslinked anion exchange resin is extremelyfavorable as a medicinal phosphorus adsorbent since the resin does notshow, by adsorbing glycocholic acid, an adverse effect to decreaseunnecessarily blood cholesterol values in renal failure or otherpatients.

[0051] The crosslinked anion exchange resin of the present invention maybe used as it is as a medicinal phosphorus adsorbent, in particular asan effective ingredient of a preventive and/or therapeutic agent ofhyperphosphatemia, but is preferably blended with other commonpharmaceutical additives into a formulation by the process well known inthe art. The pharmaceutical formulations include tablets, capsules,granules, powders, pills, troches, liquids, etc., and are orallyadministered.

[0052] The medicinal composition for oral administration can beformulated according to the processes well known in the art, forexample, by blending, filling, tabletting, etc. Additionally, theeffective ingredient may be dispersed by repeated blending operationsinto a medicinal composition containing a large amount of fillers. Forexample, tablets or capsules for oral administration are preferablyprovided as a unit medicine, and may contain pharmaceutical supportscommonly used, such as binders, fillers, diluents, tabletting agents,lubricants, disintegrants, coloring agents, flavoring agents and wettingagents, etc. The tablets may be, for example, coated with a coatingagent into coat tablets according to the process well known in the art.

[0053] Preferable examples of the filler include cellulose, mannitol,lactose, etc., and disintegrants such as starch, polyvinylpyrrolidone,starch derivatives such as sodium starch glycolate, etc., or the like,and lubricants such as sodium laurylsulfate, etc., may be also used asthe additives for the pharmaceutical formulations.

[0054] As liquid formulations are provided medicinal compositions of,for example, aqueous or oil-based suspension, solution, emulsion, syrup,elixir, etc, or as dried medicines are provided medicinal compositionsthat can be redissolved before use in water or an adequate solvent. Tothe liquid formulation may be added the additives well known in the art,including precipitation inhibitors such as sorbitol, syrup,methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose,aluminum stearate gel, hydrogenated edible fat, etc.; emulsifiers suchas lecithin, sorbitan monooleate, gum acacia, etc.; oily esters such asalmond oil, rectified coconut oil (including edible oil), glycerinesters, etc.; nonaqueous solvents such as propionglycol (sic), ethylalcohol, etc.; and preservation agents such as p-hydroxybenzoicmethylester, sorbic acid, etc., as well as flavor agents or coloringagents known in the art if desired.

[0055] In formulations containing the medicinal composition for oraladministration above, for example, in tablets, capsules, granules,powder, etc., the crosslinked anion exchange resin is usually containedin an amount of 5 to 95 mass %, preferably in an amount of 25 to 90 mass%. The medicinal phosphorus adsorbent of the present invention isparticularly useful for prevention and/or treatment of hyperphosphatemiaderived from diseases associated with renal function disorders, and inparticular for prevention and treatment of hyperphosphatemia accompaniedwith renal function disorders. The dosage of the preventive and/ortherapeutic agent may be properly determined according to the age,health condition, weight, degree of disease, kind and frequency of theother therapies and treatments concomitantly proceeding, nature of thedesired effect, etc., of the patient. The dosage is generally 1 to 60 gas an effective ingredient per adult a day, and the medicine isrecommended to be administered once or several times divided a day.

[0056] The preventive and/or therapeutic agent of hyperphosphatemia ofthe present invention decreases a phosphorus concentration in blood, andthus an amount of phosphorus excretion into urine. Accordingly, it isanticipated that the preventive and/or therapeutic agent of the presentinvention is effective for prevention and/or treatment, not only ofhyperphosphatemia, but of renal function disorders, chronic renalfailure, dialysis, hypocalcemia, excessive secretion of parathyroidhormone (PTH), suppression of vitamin D activation, ectopiccalcification, etc., which are thought to have hyperphosphatemia as thecause of the disease.

[0057] Furthermore, it is also anticipated that the preventive and/ortherapeutic agent of the present invention is effective for preventionand treatment of PTH increase caused by hyperphosphatemia, secondaryhyperparathyroidism accompanied with a decline in vitamin D, renal bonedysplasia, uremia, central and periphery neuropathy, anemia, myocardialfailure, hyperlipemia, glucose metabolism abnormality, itching disease,skin ischemic ulcer, anemia, tendon laceration, sexual dysfunction,muscular disorder, growth delay, cardiac conduction disturbance,pulmonary diffusion disturbance, arteriosclerosis, immune deficiency,etc.

EXAMPLE

[0058] Hereinafter, the present invention will be described in moredetail referring to EXAMPLES, but the following EXAMPLES are notintended to limit the present invention and all modifications within arange of the scope of the present invention are embraced in the presentinvention. Meanwhile, crosslinked anion exchange resins were preparedaccording to the methods described below. Physical properties such asnumber averaged molecular weight and the like were obtained referring tothe product catalogues of Nippon Shokubai Co., Ltd. Additionally,calcium carbonate described in the Pharmacopoeia of Japan was used.

EXPERIMENTAL EXAMPLE 1 (PREPARATIVE EXAMPLE 1)

[0059] Into a 500 ml separable flask containing 100.0 g ofpolyethyleneimine (“EPOMIN SP-006”; number averaged molecular weight600; amine value 20 mg eq/g-polymer; Nippon Shokubai Co., Ltd.) wasadded dropwise while stirring at 30° C. under a nitrogen atmosphere,17.7 g of methyl acrylate (8.8 mol % with respect to the total moles ofamino groups and/or imino groups in polyethyleneimine) over a period of3 hours (mainly the Michael addition reaction proceeded). After thedropwise addition, the mixture was heated to 70° C. and stirred for 2.5hours to promote the reaction (an amide-bond forming reaction). Afterconfirming the mixture being gelated (by the progress of crosslinking),the mixture was cooled to 30° C. and cured at the same temperature for15 hours. The mixture was separated from the separable flask and curedfor additional 1 month at room temperature.

[0060] The crosslinked anion exchange resin thus obtained was crushedand poured into 778 ml of 3N aqueous hydrochloric acid solution and theresulting mixture was stirred for 24 hours. The crosslinked anionexchange resin hydrochloride obtained was collected by filtration. Thefiltered resin was washed repeatedly with water and then poured into 10L of water, and the mixture was stirred for 24 hours. The filtered resinwas collected by filtration and lyophilized to yield crosslinked anionexchange resin No. 1.

EXPERIMENTAL EXAMPLE 2 (PREPARATIVE EXAMPLE 2)

[0061] According to the procedure described in EXPERIMENTAL EXAMPLE 1except that 44.3 g of methyl acrylate (22.1 mol % with respect to thetotal moles of amino groups and/or imino groups in the followingpolyethyleneimine) was added dropwise into a 500 ml separable flaskcontaining 100.0 g of polyethyleneimine same as that used inEXPERIMENTAL EXAMPLE 1, “EPOMIN SP-006”, the Michael addition,amide-bond forming and curing reactions were conducted. The crosslinkedanion exchange resin thus obtained was crushed and poured into 664 ml of3N aqueous hydrochloric acid solution and the resulting mixture wasstirred for 24 hours. The crosslinked anion exchange resin hydrochlorideobtained was collected by filtration. The filtered resin was washedrepeatedly with water, and then poured into 10L of water and the mixturewas stirred for 24 hours. The filtered resin was collected by filtrationand lyophilized to yield crosslinked anion exchange resin No. 2.

EXPERIMENTAL EXAMPLE 3 (PREPARATIVE EXAMPLE 3)

[0062] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine (“EPOMIN SP-018”; number averaged molecular weight1800; amine value 19 mg eq/g-polymer; Nippon Shokubai Co., Ltd.), wasadded, dropwise while stirring at 2° C. or lower under a nitrogenatmosphere, 10.8 g of epichlorohydrin (10.0 mol % with respect to thetotal moles of amino groups and/or imino groups in polyethyleneimine),and the mixture was stirred for additional 2 hours. After the stirringwas terminated, the mixture was heated to 30° C. and reacted for 1.5hours and at 50° C. for additional 1 hour. After confirming the mixturebeing gelated, the mixture was further heated to 60° C. and reacted foradditional 1 hour. After the reaction was completed, the mixture wascured at 70° C. for 24 hours. The crosslinked anion exchange resin thusobtained was crushed and poured into 384 ml of 3N aqueous hydrochloricacid solution and the resulting mixture was stirred for 24 hours. Thecrosslinked anion exchange resin hydrochloride obtained was collected byfiltration. The filtered resin was washed repeatedly with water and thenpoured into 10L of water and the mixture was stirred for 24 hours. Thefiltered resin was collected by filtration and lyophilized to yieldcrosslinked anion exchange resin No. 3.

EXPERIMENTAL EXAMPLE 4 (PREPARATIVE EXAMPLE 4)

[0063] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine (“EPOMIN SP-018”) was added, while stirring at 2° C.or below under a nitrogen atmosphere, 16.1 g of epichlorohydrin (15.0mol % with respect to the total moles of amino groups and/or iminogroups in polyethyleneimine) and the mixture was stirred for 4 hours.After the stirring was terminated, the mixture was heated to 30° C. andreacted for 1.5 hours and at 50° C. for additional 1 hour. Afterconfirming the mixture being gelated, the mixture was further heated to60° C. and reacted for additional 1 hour. After the reaction wascompleted, the mixture was cured at 70° C. for 24 hours. The crosslinkedanion exchange resin thus obtained was crushed and poured into 362 ml of3N aqueous hydrochloric acid solution and the resulting mixture wasstirred for 24 hours. The crosslinked anion exchange resin hydrochlorideobtained was collected by filtration. The filtered resin was washedrepeatedly with water, and then poured into 10L of water and the mixturewas stirred for 24 hours. The filtered resin was collected by filtrationand lyophilized to yield crosslinked anion exchange resin No. 4.

EXPERIMENTAL EXAMPLE 5 (PREPARATIVE EXAMPLE 5)

[0064] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine, “EPOMIN SP-006”, was added, while stirring at 2° C.or lower under a nitrogen atmosphere, 16.1 g of epichlorohydrin (15.0mol % with respect to the total moles of amino groups and/or iminogroups in polyethyleneimine) and the mixture was reacted for 3.5 hours.The mixture was heated to 30° C. and reacted for 1 hour and then at 50°C. for additional 2 hours. After confirming the mixture being gelated,the stirring was terminated and the mixture was heated 60° C. andfurther reacted for 1 hour. After the reaction was completed, themixture was separated from the flask and cured at 70° C. in a hot-airdrier for 24 hours. The crosslinked anion exchange resin thus obtainedwas crushed and poured into 362 ml of 3N aqueous hydrochloric acidsolution and the resulting mixture was stirred for 24 hours. Thecrosslinked anion exchange resin hydrochloride obtained was collected byfiltration. The filtered resin was washed repeatedly with water, andthen poured into 10L of water and the mixture was stirred for 24 hours.The filtered resin was collected by filtration and lyophilized to yieldcrosslinked anion exchange resin No. 5.

EXPERIMENTAL EXAMPLE 6 (PREPARATIVE EXAMPLE 6)

[0065] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine (“EPOMIN SP-200”; number averaged molecular weight10,000; amine value 18 mg eq/g-polymer; Nippon Shokubai Co., Ltd.) wasadded dropwise while stirring at 50° C. under a nitrogen atmosphere,11.6 g of ethyl acrylate over a period of 0.5 hour. After the dropwiseaddition, the mixture was reacted at 50° C. until it became solidified.After confirming the mixture being solidified, the mixture was furtherheated to 60° C. and reacted for additional 1 hour. After the reactionwas completed, the mixture was cured at room temperature for 72 hours.The reaction product (5 g) was poured into 100 ml of 0.36N aqueoushydrochloric acid solution, and the resulting mixture was stirred for 24hours and filtered. The filtered solid was rinsed in 400 ml of water,filtered and lyophilized to yield crosslinked anion exchange resin No.6.

EXPERIMENTAL EXAMPLE 7 (COMPARATIVE PREPARATIVE EXAMPLE 1)

[0066] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine, “EPOMIN SP-018” and 113.5 g of water was addeddropwise while stirring at 30° C. under a nitrogen atmosphere, 10.8 g ofepichlorohydrin (10.0 mol % with respect to the total moles of aminogroups and/or imino groups in polyethyleneimine) over a period of 10minutes. After the dropwise addition, the mixture was reacted for 0.5hour. After confirming the mixture being gelated, stirring wasterminated and the. mixture was heated to 60° C. and reacted foradditional 1 hour. After the reaction was completed, the mixture wasseparated from the flask and cured at 70° C. in a hot-air drier for 24hours. The crosslinked anion exchange resin thus obtained was crushedand poured into 384 ml of 3N aqueous hydrochloric acid solution, and themixture was stirred for 24 hours. The crosslinked anion exchange resinhydrochloride obtained was collected by filtration. The filtered resinwas washed repeatedly with water, and then poured into 10L of water andthe mixture was stirred for 24 hours. The filtered resin was collectedby filtration and lyophilized to yield crosslinked anion exchange resinNo. 7 for comparison.

EXPERIMENTAL EXAMPLE 8 (COMPARATIVE PREPARATIVE EXAMPLE 2)

[0067] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine “EPOMIN SP-018” and 195.3 g of water was addeddropwise while stirring at 30° C. under a nitrogen atmosphere, 16.1 g ofepichlorohydrin (15 mol % with respect to the total moles of aminogroups and/or imino groups in polyethyleneimine) over a period of 15minutes. After the dropwise addition, the mixture was reacted for 1hour, and further at 60° C. for 10 minutes. After confirming the mixturebeing gelated, stirring was terminated and the mixture was reacted foradditional 1 hour. After the reaction was completed, the mixture wasseparated from the flask and cured at 70° C. in a hot-air drier for 24hours. The crosslinked anion exchange resin thus obtained was crushedand poured into 362 ml of 3N aqueous hydrochloric acid solution, and themixture was stirred for 24 hours. The crosslinked anion exchange resinhydrochloride obtained was collected by filtration. The filtered resinwas washed repeatedly with water, and then poured into 10L of water andthe mixture was stirred for 24 hours. The filtered resin was collectedby filtration and lyophilized to yield crosslinked anion exchange resinNo. 8 for comparison.

EXPERIMENTAL EXAMPLE 9 (COMPARATIVE PREPARATIVE EXAMPLE 3)

[0068] Into a 500 ml separable flask containing 25.0 gpolyethyleneimine, “EPOMIN SP-018” and 155.7 g of water, was addeddropwise while stirring at 30° C. under a nitrogen atmosphere, 11.9 g ofepichlorohydrin (22.1 mol % with respect to the total moles of aminogroups and/or imino groups in polyethyleneimine) over a period of 15minutes. After the dropwise addition, the mixture was reacted for 0.5hour and at 40° C. for 0.5 hour, and further heated to 60° C. andreacted for additional 15 minutes. After confirming the mixture beinggelated, stirring was terminated and the mixture was reacted foradditional 1 hour. After the reaction was completed, the mixture wasseparated from the flask and cured at 70° C. in a hot-air drier for 24hours. The crosslinked anion exchange resin thus obtained was crushedand poured into 166 ml of 3N aqueous hydrochloric acid solution, and themixture was stirred for 24 hours. The crosslinked anion exchange resinhydrochloride obtained was collected by filtration. The filtered resinwas washed repeatedly with water, and then poured into 10L of water andthe mixture was stirred for 24 hours. The filtered resin was collectedby filtration and lyophilized to yield crosslinked anion exchange resinNo. 9 for comparison.

EXPERIMENTAL EXAMPLE 10 (COMPARATIVE PREPARATIVE EXAMPLE 4)

[0069] Into a 500 ml separable flask containing 25.0 g ofpolyethyleneimine, “EPOMIN SP-018”, and 220.3 g of water was addeddropwise while stirring at 30° C. under a nitrogen atmosphere, 16.1 g ofepichlorohydrin (30 mol % with respect to the total moles of aminogroups and/or imino groups in polyethyleneimine) over a period of 15minutes. After the dropwise addition, the mixture was reacted for 0.75hour and at 50° C. for 1 hour, and heated further to 60° C. and reactedfor additional 20 minutes. After confirming the mixture being gelated,stirring was terminated and the mixture was reacted for additional 1hour. After the reaction was completed, the mixture was separated fromthe flask and cured at 70° C. in a hot-air drier for 24 hours. Thecrosslinked anion exchange resin thus obtained was crushed and pouredinto 149 ml of 3N aqueous hydrochloric acid solution, and the mixturewas stirred for 24 hours. The crosslinked anion exchange resinhydrochloride obtained was collected by filtration. The filtered resinwas washed repeatedly with water, and then poured into 10L of water andthe mixture was stirred for 24 hours. The filtered resin was collectedby filtration and lyophilized to yield crosslinked anion exchange resinNo. 10 for comparison.

EXPERIMENTAL EXAMPLE 11

[0070] (Measurement of Water Absorption Ratio and Phosphate IonAdsorption Property)

[0071] Water absorption ratios of the crosslinked anion exchange resinshydrochloride obtained in EXPERIMENTAL EXAMPLES 1 to 10 were determined.The measurement of the water absorption ratio was conducted as follows.Samples used for the measurement were previously converted completely totheir hydrochloride salts respectively.

[0072] A content of nonvolatile material (a mass %) in each resin samplewas determined previously. A resin sample (approximately 0.2 g) wasweighed accurately (mass b), and placed in a small bag made of nonwovenfabric. The bag was heat-sealed and immersed in pure water for 24 hours(at room temperature). Subsequently, the bag was withdrawn from waterand dehydrated by centrifugation at 1300 rpm for 3 minute in acentrifuge. The dehydrated bag containing the resin was weighed to yielda mass c. From the mass c of the bag containing the resin was subtractedthe mass (0.47 g) of the nonwoven fabric bag, and the resultingdifference was divided by the mass before water absorption (a×b), andfurther subtracted by 1 to yield the water absorption ratio. Thecompositions of respective resin samples and the results of the waterabsorption ratio measurement were summarized in TABLE 1.

[0073] The phosphate ion adsorption property was measured in thepresence of glycocholic acid, and the adsorption capacity and theselectivity were evaluated. In regard to an ion concentration in theintestinal solution, each resin sample was added at a concentration of 1mg/ml into a solution of 5 mM NaH₂PO₄ and 5 mM glycocholic acid, and theresulting mixture was adjusted to pH 6.8 by the addition of sodiumhydroxide and stirred at 37° C. for 1 hour. Subsequently, the resin wasremoved by filtration through an ultrafiltration membrane, and theconcentration of phosphate ions in the filtrate that were not adsorbedon the resin was determined by the use of an inorganic phosphorusmeasuring reagent (registered trademark “P-Test Wako”; Wako PureChemical Ind.). From the measured value, the amount of phosphorusadsorbed on the crosslinked anion exchange resin (mmol/g-resin) wascalculated. Simultaneously, the concentration of glycocholic acid whichwas not adsorbed on the resin was determined by the use of a bile acidmeasurement reagent (registered trademark “Total bile acid-Test Wako”;Wako Pure Chemical Ind.), and from the measured value, the amount ofglycocholic acid adsorbed on each resin sample (mmol/g-resin) wascalculated. The results were shown in TABLE 1. TABLE 1 Compound (A)(sic) com- Water Phosphate Glycocholic pound and a- absorptionadsorption acid adsorption Polymer Mn mount (mol %) ratio (mmol/g)(mmol/g) No. 1  PEI¹⁾ 600 MA²⁾ 8.8 29.63 0.77 2.33 No. 2  PEI 600 MA22.1 2.78 2.54 0.47 No. 3  PEI 1800 EC³⁾ 10 2.12 2.76 1.34 No. 4  PEI1800 EC 15 1.19 2.98 0.11 No. 5  PEI 600 EC 15 2.29 2.56 1.78 No. 6  PEI10000 EA⁴⁾ 10 0.82 3.55 0.19 No. 7  PEI 1800 EC⁵⁾ 10 15.04 1.76 2.55 No.8  PEI 1800 EC⁵⁾ 15 14.11 1.58 2.53 No. 9  PEI 1800 EC⁵⁾ 22.1 9.05 1.32.53 No. 10 PEI 1800 EC⁵⁾ 30 4.67 1.02 2.45

[0074] As it may be apparent from TABLE 1, EXAMPLES 7 to 10 wherein thecrosslinking reactions were conducted in aqueous solutions gave thecrosslinked resins with higher water absorption ratios even though thecompound (B) was used in larger amounts. The difference in the waterabsorption ratios is more distinguishable when the values of No. 3(EXAMPLE of the present invention) and No. 7 (COMPARATIVE EXAMPLE) bothof which have same composition, or of No. 4 (EXAMPLE of the presentinvention) and No. 8 (COMPARATIVE EXAMPLE) were compared. Further, evenwhen the compound (B) was added in a significantly higher amount in Nos.9 and 10, the water absorption ratios did not become 4.0 or less.

[0075] To examine the phosphate adsorption capacity and phosphorusselectivity, i.e., which of glycocholic acid or phosphoric acid isadsorbed more strongly, the values in TABLE 1 were redrawn in a bargraph (see, FIG. 1). In FIG. 1, the vertical line on the left sidecorresponds to the amounts of phosphoric acid (left bar in each sample)and glycocholic acid (right bar) adsorbed, while the vertical line onthe right side corresponds to the water absorption ratios shown in thesequential line. In FIG. 1, the resin samples were arranged in anincreasing order of the water absorption ratio from left. As it may beapparent from FIG. 1, the resin sample No. 6 having the lowest waterabsorption ratio has the highest phosphate ion adsorption capacity whileadsorbs almost no glycocholic acid, indicating the resin is extremelyexcellent in the phosphorus selectivity. It was also confirmed that theresins having the water absorption ratio beyond 4.0 adsorb moreglycocholic acid than phosphoric acid, and thus were not within thescope of the present invention.

[0076] Additionally, the results from the resin samples prepared frompolyethyleneimines having molecular weight of 1800 and 10000 wereredrawn as a graph in FIG. 2, similarly to FIG. 1. The graph shows moreclearly the correlation between the water absorption ratio and thephosphorus selectivity.

EXPERIMENTAL EXAMPLE 12 (PREPARATIVE EXAMPLE 7)

[0077] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine (“EPOMIN SP-018”) was added dropwise while stirring at40° C. under a nitrogen atmosphere, 12.5 g of methyl acrylate (12.5 mol% with respect to the total moles of amino groups and/or imino groups inpolyethyleneimine) over a period of 1.5 hours. After the dropwiseaddition, the mixture was heated to 70° C. and reacted for 2.5 hours.After confirming the mixture being gelated, the mixture was cured at 70°C. for additional 72 hours. The crosslinked anion exchange resin thusobtained was crushed and poured into 373 ml of 3N aqueous hydrochloricacid solution, and the mixture was stirred for 24 hours. The crosslinkedanion exchange resin hydrochloride obtained was collected by filtration.The filtered resin was washed repeatedly with water, and then pouredinto 10L of water and the mixture was stirred for 24 hours. The filteredresin was collected by filtration and lyophilized to yield crosslinkedanion exchange resin No. 11.

EXPERIMENTAL EXAMPLE 13 (PREPARATIVE EXAMPLE 8)

[0078] According to the method of EXPERIMENTAL EXAMPLE 12 except thatinto a 500 ml separable flask containing 50.0 g of polyethyleneimine,“EPOMIN SP-018” was added 15.0 g of methyl acrylate (15.0 mol % withrespect to the total moles of amino groups and/or imino groups inpolyethyleneimine), crosslinked anion exchange resin No. 12 wasobtained.

EXPERIMENTAL EXAMPLE 14 (PREPARATIVE EXAMPLE 9)

[0079] According to the method of EXPERIMENTAL EXAMPLE 12 except thatinto a 500 ml separable flask containing 50.0 g of polyethyleneimine,“EPOMIN SP-018”, was added 17.5 g of methyl acrylate (17.5 mol % withrespect to the total moles of amino groups and/or imino groups inpolyethyleneimine), crosslinked anion exchange resin No. 13 wasobtained.

EXPERIMENTAL EXAMPLE 15 (PREPARATIVE EXAMPLE 10)

[0080] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine (“EPOMIN SP-200”; number averaged molecular weight10,000; amine value 18 mg eq/g-polymer; Nippon Shokubai Co., Ltd.) wasadded dropwise while stirring at 50° C. under a nitrogen atmosphere,10.0 g of methylacrylate (10 mol % with respect to the total moles ofamino groups and/or imino groups in polyethyleneimine) over a period of1 hour. After the dropwise addition, the mixture was heated to 70° C.and reacted for 2.5 hour, and after confirming the mixture beinggelated, the mixture was cured at 70° C. for additional 72 hours. Thecrosslinked anion exchange resin thus obtained was crushed and pouredinto 405 ml of 3N aqueous hydrochloric acid solution, and the mixturewas stirred for 24 hours. The crosslinked anion exchange resinhydrochloride obtained was collected by filtration. The filtered resinwas washed repeatedly with water, and then poured into 10L of water andthe mixture was stirred for 24 hours. The filtered resin was collectedby filtration and lyophilized to yield crosslinked anion exchange resinNo. 14.

EXPERIMENTAL EXAMPLE 16 (PREPARATIVE EXAMPLE 11)

[0081] Into a 500 ml separable flask containing 50.0 g ofpolyethyleneimine, (“EPOMIN SP-200”) was added dropwise while stirringat 50° C. under a nitrogen atmosphere, 15.0 g of methyl acrylate (1 mol% with respect to the total moles of amino groups and/or imino groups inpolyethyleneimine) over a period of 1.5 hours. After the dropwiseaddition, the mixture was heated to 70° C. and reacted for 2.5 hours andafter confirming the mixture being gelated, the mixture was cured at 70°C. for additional 72 hours. The crosslinked anion exchange resin thusobtained was crushed and poured into 362 ml of 3N aqueous hydrochloricacid solution, and the mixture was stirred for 24 hours. The crosslinkedanion exchange resin hydrochloride obtained was collected by filtration.The filtered resin was washed repeatedly with water, and then pouredinto 10L of water and the mixture was stirred for 24 hours. The filteredresin was collected by filtration and lyophilized to yield crosslinkedanion exchange resin No. 15.

EXPERIMENTAL EXAMPLE 17

[0082] (Measurement of Phosphate Ion Adsorption at Ion Concentration inIntestinal Solution)

[0083] Phosphate ion adsorption properties of calcium carbonate that hasbeen used as a medicinal oral phosphorus adsorbent and a crosslinkedanion exchange resin of the present invention in the presence ofglycocholic acid were examined. In regard to an ion concentration in theintestinal solution, crosslinked anion exchange resin No. 2 obtainedEXPERIMENTAL EXAMPLE 2 and calcium carbonate were added respectively insolutions of 5 mM NaH₂PO₄ and 5 mM glycocholic acid at a concentrationof 1 mg/ml, and the resulting mixtures were adjusted to pH 6.8 by theaddition of sodium hydroxide and stirred at 37° C. for 1 hour.Subsequently, the resin was removed by filtration through a filter, andthe amount of phosphoric acid that was not adsorbed on the resin wasdetermined by the use of an inorganic phosphorus-measuring reagent(registered trademark “P-Test Wako”; Wako Pure Chemical Ind.). From themeasured value, the amount of phosphorus adsorbed on the crosslinkedanion exchange resin sample (mmol/g-resin) was calculated.Simultaneously, the amount of glycocholic acid which was not adsorbed onthe resin was determined by the use of a bile acid measurement reagent(registered trademark “Total bile acid-Test Wako”; Wako Pure ChemicalInd.), and from the measured value, the amount of glycocholic acidadsorbed on the resin sample (mmol/g resin) was calculated. The resultswere shown in FIG. 3.

[0084] It is apparent that crosslinked anion exchange resin No. 2 has alarger phosphoric acid adsorption capacity than calcium carbonate and aextremely low absorption capacity of glycocholic acid

EXPERIMENTAL EXAMPLE 18

[0085] (Effects on Phosphorus Amount in Blood and Urine of Normal Rats)

[0086] Suppressive effects of crosslinked anion exchange resin No. 2 andcalcium carbonate to the increase in a phosphorus amount in urine havebeen examined using male SD rats (8 weeks old). First, feedstuffcontaining 0.3 mass % of phosphorus (20 g/rat/day) was fed for 7 days.Subsequently, the feedstuff containing 0.58 mass % of phosphorus (20g/rat/day) was blended with 0.6 g of crosslinked anion exchange resinNo. 2 obtained in EXPERIMENTAL EXAMPLE 2 or calcium carbonate, and themixed feedstuff was administered for 5 days.

[0087] Before and 5 days after the first administration, urine for 24hours was collected and the phosphorus amount in the urine wascalculated from the concentration of phosphorus and the volume of urine.The phosphorus concentration in urine was determined by the use of aninorganic phosphorus-measurement reagent (registered trademark “P-testWako”; Wako Pure Chemical Ind.).

[0088] From the differences in the phosphorus amount before and 5 daysafter the first administration, urinary phosphorus excretions (increasesin phosphorus excretion into urine [mg/24 hours]) were calculated andcompared with those of the non-administered group (control). Meanwhile,6 rats are used in each group.

[0089] The results are shown in FIG. 4. The increase of urinaryphosphorus excretion was suppressed with a statistically significantdifference in the calcium carbonate-administered group, compared to thecontrol group. In the group administered with the crosslinked anionexchange resin was also statistically suppressed the increase of urinaryphosphorus excretion, and the effect was greatly larger than that in thecalcium carbonate-administered group. Meanwhile in the FIGURE, * and **indicate that the group has a significant difference from the control(respectively, P<0.05 and P<0.01 in Student's T-Test). Additionally, #indicates that the group has a significant difference from the calciumcarbonate-administered group (P<0.05 and P<0.01, Student's T-Test).

EXPERIMENTAL EXAMPLE 19

[0090] (Effects on Phosphorus Concentration in Blood and Renal Functionof ⅚ Nephrectomized Rats)

[0091] The effects of crosslinked anion exchange resin and calciumcarbonate on the suppressive action on phosphorus amount in urine and onrenal functions were examined using male SD rats (9 weeks old). First, ⅔of the left kidneys of male SD rats and after a week, all of the rightkidneys thereof were removed to give ⅚ nephrectomized rats. After 1week, feedstuff blended with calcium carbonate or crosslinked anionexchange resin No. 2 obtained in EXPERIMENTAL EXAMPLE 2 wasadministered. As the powdery feedstuff for rats was used MF manufacturedby Oriental Yeast Co. Ltd., and the dosage was 15 g of the feedstuffcontaining 0.3 g of calcium carbonate and crosslinked anion exchangeresin No. 2, respectively. After 12 weeks from the day the ⅚nephrectomized rats were obtained, blood samples were withdrawn from thetail veins of the rats, and the phosphorus concentrations in blood weredetermined by an inorganic-measurement reagent (P-Test, Wako, mentionedabove). Additionally, before and after 12 weeks from the day the ⅚nephrectomized rats were prepared, urines were collected respectivelyfor 24 hours, and protein concentrations in the urines were determinedby a protein measurement reagent (Protein Assay Kit, Bio-Rad).Meanwhile, the number of rats in each group used for experiment was 9respectively.

[0092] The results were shown in FIG. 5 and FIG. 6. As shown in FIG. 5,the calcium carbonate-administered group did not have a statisticallysignificant difference in blood phosphorus concentration, compared tothe control. But, the group administered with crosslinked anion exchangeresin No. 2 had a significant decrease in blood phosphorusconcentration. On the other hand as shown in FIG. 6, after 12 weeks frompreparation of the ⅚ nephrectomized rats, a marked increase in proteinexcretion into urine was observed in the control, indicating thedeterioration of renal function, while the increase in protein excretioninto urine was significantly suppressed in the calcium carbonateadministered group compared to the control. In the group administeredwith crosslinked anion exchange resin No. 2, the increase in proteinexcretion into urine was also significantly suppressed, and the effectwas greater than that of the calcium carbonated-administered groupindicating an excellent suppressive effect thereof to the deteriorationof renal function.

INDUSTRIAL APPLICABILITY

[0093] A crosslinked anion exchange resin or a salt thereof of thepresent invention is excellent in its phosphorus adsorption capacity andthus can be used as a phosphorus adsorbent for purification of water inponds, lagoons and the like. Further, it adsorbs efficiently phosphorusin a selective manner even in the presence of glycocholic acid or thelike in the gastrointestinal tracts, and thus could decrease markedly aphosphorus concentration in blood and a phosphorus excretion into urine,consequently suppressing deterioration of renal functions. Therefore,the crosslinked anion exchange resin or the salt thereof of the presentinvention is also useful as a medicinal phosphorus adsorbent, and as apreventive and therapeutic agent of hyperphosphatemia.

What is claimed is:
 1. A crosslinked anion exchange resin or a saltthereof characterized by being obtained by reacting a polymer (A) havingamino and/or imino groups in the total number of two or more permolecule with a compound (B) having two or more functional groupscapable of reacting with amino and/or imino groups contained in thepolymer (A), and by having a water absorption ratio of 4.0 or less.
 2. Acrosslinked anion exchange resin or a salt thereof characterized bybeing obtained by reacting a polymer (A) having amino and/or iminogroups in the total number of two or more per molecule with a compound(B) having two or more functional groups capable of reacting with aminoand/or imino groups contained in the polymer (A) in the absence of asolvent or in a presence of a non aqueous solvent.
 3. A crosslinkedanion exchange resin or a salt thereof according to claim 1 or 2,wherein said polymer (A) has a number averaged molecular weight of 200or more.
 4. A crosslinked anion exchange resin or a salt thereofaccording to one of claims 1 to 3, wherein said polymer (A) is one ormore polymer selected from the group consisting of polyalkyleneimine,polyallylamine, polyvinylamine and allylamine-vinylamine copolymer.
 5. Aphosphorus adsorbent characterized by comprising a crosslinked anionexchange resin or a salt thereof according to one of claims 1 to
 4. 6. Aphosphorus adsorbent according to claim 5 for use as a medicine.
 7. Apreventive and/or therapeutic agent of hyperphosphatemia, characterizedby comprising a crosslinked anion exchange resin or a pharmaceuticallyacceptable salt thereof according to one of claims 1 to 4.